Trivalent chromium (Cr3+) enhances glucose metabolism. Recent Cr3+ studies by our group provide new perspective on the molecular action of Cr3+. We have found that Cr3+ activates glucose transporter GLUT4 trafficking and enhances insulin-stimulated glucose transport in 3T3-L1 adipocytes via a cholesterol- dependent mechanism. Although these data are consistent with Cr3+ exerting a positive effect on the glucose transport system and lowering elevated blood glucose in type 2 diabetic individuals, a confounding issue is that non-diabetic individuals do not experience a change in blood glucose following Cr3+ treatment. While available evidence implicates that Cr3+ has the most dramatic impact on risk factors in overweight insulin-resistant subjects, the cellular and molecular factor(s) contributing to "Cr3+ sensitivity" are not known. The central hypothesis of this proposal is that pathological nutrient states such as hyperglycemia, hyperinsulinemia, and hyperlipidemia induce cell surface changes that reduce insulin sensitivity but augment Cr3+ sensitivity. Utilizing well-characterized in vitro adipocyte and skeletal muscle model systems, Aim 1 studies will focus on defining nutrients that invoke cellular hypercholesterolemia and insulin resistance. Aim 2 investigations will concentrate on elucidating the mechanism(s) coupling nutrient states to cellular cholesterol imbalance. A combination of molecular, microscopic, and biochemical approaches will be employed in these studies. Results will be significant because they are expected to provide new targets for the preventative and therapeutic interventions needed by the rapidly expanding type 2 diabetic and impaired glucose tolerant population in this country. Furthermore, it is expected that these proposed studies will have a fundamental impact on our understanding of a diverse range of other Cr3+-treatable pathologies. For example, accumulating epidemiological data that significantly correlates hypercholesterolemia and insulin resistance also seems to identify additional cholesterol-related abnormalities, such as cardiovascular disease (CVD) and cognitive dysfunction. In this regard the significance of Cr3+ supplementation in CVD and neurological disorders such as Alzheimer's disease, atypical depression, and dementia emphasizes the importance of understanding what makes individuals responsive to Cr3+ supplementation. In closing, this project is relevant to public health because it will deepen understanding into nutritional abnormalities that confer cellular responsiveness to Cr3+ and thus, the studies will pioneer a new connection coupling Cr3+ treatment in the prevention of disease and on the maintenance of health. New insight will advance the field of human nutritional resources aimed at creating medically and economically beneficial health care. [unreadable] [unreadable] [unreadable] [unreadable]